RL648_81: Synthesis and Evaluation of Potent KCNQ2/3-specific Channel Activators

@attheedgeofscience

Since you have resources none of us do, is there any info on when or if this is going into human trials?

 

This is really interesting stuff! It's important to stay positive with T and this is something that gives hope to people. I remember when news of Autifony came out, that was what gave me hope which evidently led to me habituating the first time. I know Autifony didn't go quite so well but hearing about this gives me that same hope! A treatment is on the way.

 

Absolutely not. First a pharma company needs to be selected for the process, and, then the process - the clinical trial, that is - needs to be initiated. Based on previous history (with other compounds), and also the importance of neurological disorders, I can imagine that a pharma company will be found for RL-81. For instance, besides SF0034, it would seem that there was also involvement from the Pittsburgh School of Medicine when the following series of compounds...

Imidazo(4,5-b) pyridin-2-yl amides as kv7 channel activators

...were patented (and that pipeline sits with Knopp Biosciences - information I have already shared on TinnitusTalk previously).

About getting things underway, well, as always remember that there is no sense of urgency within the medical establishment unless it concerns epidemics (e.g. Flu, Ebola). So do not expect this development to suddenly get executed in one-third of the usual timeline.

Perhaps, the best the tinnitus community can do for itself is focus on the social media angle i.e. promotion/awareness of tinnitus topics. For instance, those who pay a little attention to the TinnitusTalk news feed will notice that the "ratings : follower"-ratio is very high (compare it with e.g. the ATA or BTA - organizations that have a proper marketing resource and budget for that). This is a sign of competency on the part of those who did that social media work (I wonder who it was...???). Imagine now that the +1 million annual visitors of TinnitusTalk donated just one tiny dollar each - that would allow TinnitusTalk to run some serious campaigns of awareness.

Last but not least, I do think that the tinnitus community is getting ahead of itself sometimes - I don't think you will find many other forums (for other disease areas) where pre-clinical trial developments are given such attention (e.g. even for deadly diseases such as cancer). Maybe if it was in phase-III and possibly phase-II - then yes, there begins to be room for optimism. But phase-0...?

 

Thank you, informative as usual.
I wouldn't really call it an optimism but rather pure desperation since we must be the only community that's left with no formal treatment that actually helps (this doesn't include hocus pocus snake oils).
I guess we need a ray of hope coming from somewhere, anywhere, even though landing is very painful when things go to waste like autifony!
Regarding money, years ago I was wondering the same! If every person with t would give $1 we would be the strongest forse ever seen.
And as you said even if every TT visitor would donate just $1... wow!
Maybe a food for thought!

 

Dan Informed me about this new drug approved for tinnitus

Researchers at the University of Pittsburgh School of Medicine and Arts & Sciences have designed a more effective version of an FDA-approved epilepsy drug with the potential for fewer side effects, according to a study published on March 22 in Molecular Pharmacology. The experimental agent also could prove to be a treatment for tinnitus and other disorders caused by volatile neural signaling.

Distinguished University Professor of Chemistry at Pitt, rationally redesigned several structural components of retigabine to further increase its potency. Retigabine works by activating all five types of potassium transport channels in the KCNQ category, but only two of the potassium channels, KCNQ2/3, are important for stabilizing the cell membrane of brain cells involved in hyperexcitability-related disorders, such as epilepsy and tinnitus, Dr. Tzounopoulos explained. The new compound, known as RL648_81 ("RL-81"), targets just those channels.

https://www.sciencedaily.com/releases/2016/03/160330102848.htm

 

It sound good. Is this drug already tested on mice, rats or similar to humans?

 

The lab tests mentioned to figure out the relative strengths of different research chemicals use rodent models i.e mice.

However, how these drugs seem to react on paper after rodent testing is often very different when they are given to higher primates and humans.

Even if this drug works it'll take a decade to come online and available.

Don't hold your breath, habitating is the only real
option...don't be chasing unicorns ladies and gentlemen.

 

That statement should get you lots of friends here...

 

Lucky I'm not looking for friends aha...

I think a non drug based treatment would be the best solution in the long run anyway...if one is possible some day.

So say it works and magically its available next year... you're still basically hooked on the medicine for life and what if your tolerance goes up and it become ineffective after 1 or 2 years? Many would top themselves after being thrown back into the tinnitus mental meat grinder.

That's not even going into side effects like blindness, impotence or whatever may come up.

Deal with it now!right now inside your own head. Don't let it set the terms of your mental health. Your response is what ruining your life...shit how.many noises do we repress living in a busy industrial society?

The washing machine, tap,fridge,clock etc.

Think about it

 

You will definitely get lots of friends with that statement.

Last year I attended a business accelerator (as a mentor for start-ups). One of the weekly speakers there said:

"Assumptions is the mother of all fuck-ups" (i.e. don't assume anything - a comment the speaker made in relation to customer profiling and customer needs).

I have now passed this advice on to you (and free-of-charge). A permanent reduction in tinnitus intrusion (even after tapering off) Kv-channel medication is a possibility.

Agree. Incidentally, what made you sign-up with this forum, I might ask?

 

Man you're so clever . Its all black and white.

What you say, is true for "normal" T...Habituation will happen sooner or later, if the person is able to habituate. So it basically doesnt matter, its not like a person if fighting against it. Before I got debilitating T, I had a normal one toned T for more than 7 years. I habituated after a year and life was okay. So I know both sides of T.

The weak side of your post is. You (and many other people on this board) simple forget (or chose to forget ) that there are debilitating cases of Tinnitus, which basically force you to kill yourself (like in mine case and a handfull of other on this board). A multiple T so severe that it cant be habituated to.

And no, its not the response thats killing "us", but severeal loud sounds at once, reactive T, Hyperacusis, ear pain, hearing loss, vibrating head. All these at once will drain you, crush you and make your life impossible. Its physically exhausting, not your reaction.

So please, people need to stop acting like theyre some kind of habituation heroes (= "every T is the same, its your reaction!!! LOOK AT ME I DID IT !" ) because they have overcome mild T. As ATEOS said, stop assuming.
Theres basically not a single case of on this board of people with really severe reactive , T + H + ear pain who got better in time. And THOSE people need a real treatment, not the ones who write success stories after 3 weeks.

I would gladly take pills all my life to stop this torture.

"the washing machine" is one of the sounds in my head.

"Think about it."

 

Firstly, they formed a scientific answer as to why trobalt causes retinal pigment changes and they know how to avoid these issues.

"As a result, the FDA limited its use to patients who have not responded to alternative treatments. The undesirable side effects are likely due to the poor selectivity of retigabine among KCNQ2-5 channels as well as metabolic degradation products of its aniline ring. For example, retigabine activates KCNQ4 and KCNQ5, which are not involved in the pathology of hyperexcitability-related disorders. KCNQ4 is the primary potassium channel in the smooth muscle of the bladder, where it regulates contractility (Greenwood and Ohya, 2009; Jentsch, 2000). Activation of KCNQ4 leads to membrane hyperpolarization and results in significantly reduced contractility, which may be the cause for urinary retention associated with the use of retigabine. Moreover, a form of dominant deafness arises from loss of function of KCNQ4 (Kharkovets et al., 2000), and therefore opening of these channels may affect hearing."

"Because of its enhanced specificity over retigabine, RL648_81 is expected to have fewer side effects.

Although the mechanism by which retigabine-mediated toxicity influences skin and retina remains poorly understood, one hypothesis is that UV radiation may cause photodegradation and oxidation of retigabine’s aniline ring, which may lead to the formation of colored deposits in skin and eyes. The incorporation of electron-withdrawing highly fluorinated substituents significantly

Molecular Pharmacology Fast Forward. Published on March 22, 2016 as DOI: 10.1124/mol.115.103200 This article has not been copyedited and formatted. The final version may differ from this version.

reduces the highest occupied molecular orbital energy of RL648_81 (-8.33 eV) vs. retigabine (- 8.06 eV), and thus should render the former compound less prone to formation of reactive metabolites (Kawai et al., 2007). The trifluoromethylated RL648_81 is also expected to be more resistant to photodegradation and therefore less toxic to the eye and to the skin"


They know what causes tinnitus development
"Genetic mutations in either KCNQ2 or KCNQ3 subunits are linked to benign familial neonatal convulsions, whereas noise-induced reduction in KCNQ2/3 channel current leads to development of tinnitus in mice"

TRT and habituation doesn't work for everyone, as their tinnitus is too loud, as mine was before trobalt. I contribute trobalt to saving my life, as it's lowered my tinnitus substantially.

My point is, I don't want people to die and I don't want people to needlessly to suffer. If this drug can lower tinnitus and possibly cure people, then this is something I support and I'd rather not be phlegmatic like you are.


Look, this drug is something I am excited for as are others. To discredit a drug before you've tried it, is rather scatterbrained and it's like you don't want something to come out.

Anyway, I hope others read this and realises this is truly exciting and your comments don't discourage their enthusiasm and eagerness for this drug to come out.

 

I signed up because I have had really loud tinnitus in my left ear since Feb 2013.

By the end of 2013 I started having tremors in my right.

Tones change daily and volumes as well.

It nearly destroyed my marriage and I had a break down of sorts whereby I became very strange after perlonged sleep deprivation.

So ladies and gentleman I have the right to an opinion.

I have tried a hundred or more meds, supps and what not and only became more frustrated,anxious and depressed.

Sorry Dannyboy I'm not goning to advocate trying every chem or research chemical that may or may not help to the tinnitus community.

If in a decade this med turns out to be helpful...you know I might just try it...but I'm not holding my breath and you shouldn't be either.

But my point to all tinnitus suffers is that we all carry this cross inside our own heads....it is how we react to it that defines the level of pain it causes ourselves and those around us.

I still have tinnitus...bad. But I decided after being at the end of my tether for nearly two or more years that I was going to have to change my coping strategy because chasing every new unicorn I heard about wasn't making my life any happier.

I had become a self absorbed irritable husband and distant father because of it.

So I take melatonin every night before sleep and turn on a light masker that doesn't fully mask it but helps....and that's all I can currently do whether I.like it or not.

 

I'll admit my remarks were a tad too flippant but I suppose I thought people knew me here.

However its been months since I've posted...so many of you thought I was an ignorant asshole belittling your suffering but I'm not.

Sorry if I was misunderstood

 

This is the best place to be if you want to be understood. The effect T has on people's lives and the lack of regularly effective objective treatments (at the moment) can easily trap us sufferers in a negative mindset and make us immediately skeptical of any positive progress...

My view on things like RL648_81, AM_101, and Retigabine, and this is just my view, is that these drugs shouldn't immediately be interpreted as potential cures to blindly look forward to, but as stepping stones towards a better understanding of the mechanisms behind T. These proposed treatments still represent real progress and are, objectively, purely good things. These newly developed medications show that people out there DO care and ARE trying very hard to help us. I mean, they're dedicating their lives to developing treatments that they know may not even work. That's just how research in any scientific field works. At it's very basest level, any scientific research is a series of experiments.

But I mean, what the hell, if it DOES wind up being an effective treatment for T, then man that's freaking awesome! But, you're right; we shouldn't herald every new development in the field as a cure, it's led to disappointment more than a few times now. Keep your hopes high - but not too high.

 

This RL molecule looks like it's going to be the best shot we have so far .

Unfortunately as mentioned here the process is going to take years - 10 maybe, just to get FDA approval as testing takes time and huge amount of money and tinnitus isn't such a high priority .

However - the good news is that we can get it much earlier , in a matter of a month or two by getting it synthesized by a Chinese lab specialized in research chemicals.

I spoke to my contact who has been constantly supplying me various non-FDA approved cutting edge compounds for over 8 years with high purity and good service.


I sent them the chemical description and the good news is that they can get a first batch synthesized - the cost is not cheap but still doeable - and once the first 10g are sythetized they can figure out ways to bring costs down for larger amounts on a regular basis.

Phase 2-3 testing takes years and there is no reasons to wait as long provided you are willing to take a risk and be your own test experiment .

I also plan to do a basic 1 month animal test on Rodents by feeding them 10 times the planned doses (100mg/day) by body weight just to see if no major harmful effect happens.

I live alone btw! ..

We can also get another independent lab to test the authenticity and purity of the chemical supplied.

Feel free to pm me if interested I need to see how many people we could potentially get to start the ball rolling .
Again - this is a use-it-at-your
-own-risk proposal, if anything happens you cannot sue, you are basically on your own .


I plan on starting at 10mg a day for some time then get regular liver/Kidney values tests and increase from there .

If the effectiveness is really 15 times RTG then we can perhaps use only 100mg a day to get 1.5 times the effect with hopefully less side effects .

 

@Bobby B That's an interesting proposal, but I would personally want to wait at least until the phase 1 trials (safety and dosage study) are completed. Until there is at least some research on humans I feel it is a little to risky IMO. Once we know more about it, such as safe dosages (if it is safe), possible side effects and hopefully signs that it has the potential to actually work , having the option to try it still several years before it comes to market would be great.

 

That's a 5 years wait at least

Setting human tests will take time - phase 1 only tests for a short time frame and small group which does not prove the drug to be safe long term anyway.

The Professor isn't even going to start animal testing in 2 years ... I guess he doesn't t have T to motivate him for a faster process...
They need approval , budget and scheduling etc...

We can go around this

We can at least do the animal tests this spring and re-assess it from there

 

Yes, and I'd be willing to wait even longer to ensure it's safe. Personally I don't want to take a new brain altering drug without at least some scientific proof that it's safe. I understand you're point of view, and it'd be great to hear whether it works or not even sooner, but it'd still be a win in my books if we're able to get it in say 7 years through synthesis instead of 12 if it makes it to market (again, that's a big IF, since it very well could be a bust like aut0063)

 

Is there a way to get Chinese researchers to test the dug?

 

They will test for purity that's it - typically 98% is what they guarantee .

They are not researcher just labs that provide research chemicals for testing purposes.

We can get a spectrogram done at a different lab not an issue.

 

But how do you know the formula?
I mean this is some serious stuff!

 

The chemical formula is on the pdf in this thread

 

Bobby B when do you plan to start all of this?

 

Several people have expressed interest - there will be a small group for the first batch as its not going to be a large amount since it's going to be the first batch to be synthesized by that lab.

They can deliver the first batch in about 6 weeks once payment has been done.

Waiting for years isn't going to the name of the game here - enough of that already

 

Prof TT has been siting on the fence with SF for few years now with no indication of human trials anytime soon.
Now this new formula comes out of nowhere/somewhere and I doubt that there's any urgency to do any different.
Even though I appreciate his effort it also makes me wonder if they are just running things in circles to keep their jobs and funds coming in!
In today's world of money and corruption anything is possible

 

In reality a lot of very promising drugs are never developed due to many factors - cost of testing / approval , company business focus , legal or patent issues , funding or timing etc.. I am using some of these drugs myslef on my own body everyday - for other conditions than hearing - but the fact is those drugs I have been using for years are synthetized by Chinese labs not western pharma firms ...

In this RL study prof. T (!) used a us military grant but he would need further funding to move ahead with more testing

 

Hi Bobby B,

I was trying to find a way to PM you but I don't think I am proficient with this forum just yet.

I'd be interested in joining the group buy for the first round if still possible...

By the way, thank you for your reply on the LLLT front. I found the pulsed settings and am continuing with the therapy daily.

Thanks,

Greg

 

One would think that military would be jumping the wagon to fund this study instead of spending billions on compensations for hearing loss and tinnitus.
Weird!

 

You'd think they would. This world is rather strange. They would rather let these vets suffer and give them 'payments' than release them from suffering, plus they could prevent new cases of soldiers having tinnitus by giving them this pill, saving them millions, even billions.

Anyway, with Bobby B we could get this drug like 10 years early and could bring the prices down if we have loads of people invest in this opportunity.